NDRG2-mediated Modulation of SOCS3 and STAT3 Activity Inhibits IL-10 Production

Abstract

BackgroundN-myc downstream regulated gene 2 (NDRG2) is a member of the NDRG gene family. Our previous report indicated a possible role for NDRG2 in regulating the cytokine, interleukin-10 (IL-10), which is an important immunosuppressive cytokine. Several pathways, including p38-MAPK, NF-κB, and JAK/STAT, are used for IL-10 production, and the JAK/STAT pathway can be inhibited in a negative feedback loop by the inducible protein, SOCS3. In the present study, we investigated the effect of NDRG2 gene expression on IL-10 signaling pathway that is modulated via SOCS3 and STAT3.MethodsWe generated NDRG2-overexpressing U937 cell line (U937-NDRG2) and treated the cells with PMA to investigate the role of NDRG2 in IL-10 production. U937 cells were also transfected with SOCS3- or NDRG2-specific siRNAs to examine whether the knockdown of SOCS3 or NDRG2 influenced IL-10 expression. Lastly, STAT3 and SOCS3 induction was measured to identify the signaling pathway that was associated with IL-10 production.ResultsRT-PCR and ELISA assays showed that IL-10 was increased in U937-mock cells upon stimulation with PMA, but IL-10 was inhibited by overexpression NDRG2. After PMA treatment, STAT3 phosphorylation was decreased in a time-dependent manner in U937-mock cells, whereas it was maintained in U937-NDRG2 cells. SOCS3 was markedly reduced in U937-NDRG2 cells compared with U937-mock cells. IL-10 production after PMA stimulation was reduced in U937 cells when SOCS3 was inhibited, but this effect was less severe when NDRG2 was inhibited.ConclusionNDRG2 expression modulates SOCS3 and STAT3 activity, eventually leading to the inhibition of IL-10 production.

Novel Mechanism of Inhibition of Dendritic Cells Maturation by Mesenchymal Stem Cells via Interleukin-10 and the JAK1/STAT3 Signaling Pathway

“…Our study did not focus on effects at the protein level, for example, the implication of the suppressor of cytokine signaling (SOCS) [33]. Additionally, this study was only performed in vitro .…”

Role of interleukin-10 in breast cancer

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Prognostic significance of NDRG2 combined with EGFR patients with lung adenocarcinoma

“…Two human cDNAs, encoding NDRG3 and NDRG4, are homologous to NDRG1. These two genes, together with NDRG1 and a previously deposited cDNA (designated NDRG2), constitute the NDRG gene family [17]. Previous studies reported that NDRG2 was associated with human lung cancer, and the decreased expression of NDRG2 was correlated with a worse outcome of lung cancer patients [12,18].…”